Pulmonary arterial hypertension (PAH) is a rare but devastating disease, in which the normally low pulmonary artery pressure becomes elevated due to vaso-constriction and to the remodelling of pulmonary vessels. This in turn increases workload on the right side of the heart, causing right heart hypertrophy, fibrosis and ultimately heart failure.
Interventions used in the management of PAH are traditionally targeted on the vasculature, with the aim of enhancing vasodilation and anti-proliferation pathways. These include the prostacyclin analogues and nitric oxide (NO). However, it is increasingly recognized that in addition to the pulmonary vasculature, the right heart is also a viable therapeutic target in the treatment of PAH. PPAR β inhibitors have been shown in recent studies on animal models to reduce right heart hypertrophy without influencing pulmonary vascular remodelling.
Prostacyclin Analogues
Prostacyclin is a powerful vasodilator, produced in the body by endothelial cells. Patients with PAH are found to have low levels of prostacyclin, leading to a frequently life-threatening constriction of the pulmonary vasculature.
Natural prostacyclin has been found to be unstable in solution, and undergoes rapid degradation, making it very difficult to use for clinical applications. Over 1,000 synthetic prostacyclin analogues have been developed to date as a result. One of these, Treprostinil has demonstrated unique effectiveness in inhibiting platelet activation and as a vasodilator, and it has relatively good stability in solution compared to native prostacyclin. Other prostacyclin analogues, such as Selexipag are currently undergoing clinical trials with highly encouraging results.
Treprostinil is currently marketed in two formulations, as an infusion (subcutaneous or intravenous via a continuous infusion pump), or as an inhaled aerosol, used with a proprietary device, 4 times per day and at least 4 hours apart. The infusion is frequently associated with side effects such as severe site pain or reaction, whilst the aerosol requires a disciplined regimen on the part of patients. Attempts to develop an oral formulation have to date failed FDA regulatory approval due to the relatively adverse risk/efficiency ratio of prototypes tried so far.
Developing alternative formulations of Treprostinil, which bypass the many serious shortcomings of the continuous infusion/pump system, and which allow efficient, controlled, targeted and sustained release of the drug without the complexity of the current aerosol system, should improve patient compliance and experience of treatment, and ultimately impact on successful management of the condition.
Selexipag is currently undergoing Phase III trials. Selexipag is designed to act on IP (prostacyclin) receptors selectively, and has to date demonstrated a significant reduction in pulmonary vascular resistance within the trial cohorts studied. It is currently produced as an oral formulation, and although the administration regime is far simpler than for Treprostinil, again the development of a formulation and delivery mechanism that allows efficient, controlled, targeted and sustained release of the drug would significantly reduce side effects and improve patient compliance, ultimately impacting positively on outcome.
Nitric Oxide
Nitric oxide is known to have vasodilatory effects on the pulmonary vasculature in both humans and animals. A number of trials suggest that the effects of NO on vascular resistance are selective (ie focused on pulmonary rather than systemic), and do not cause systemic hypotension or raise methaemoglobin.
The main challenge with NO therapy is in sustaining benefit over a prolonged period. A delivery mechanism that allows controlled, sustained release of NO, such as that offered by the present invention, can substantively overcome this challenge. Formulations of NO donors (such as, but not limited to, organic nitrates, nitrite salts, s-nitrosoglutathione (GSNO), and S-Nitrosothiols) can be loaded into the delivery mechanism, which can produce sustained and controlled doses of NO when activated by the moisture in the lung.
PPAR β Agonists
The pulmonary vasoconstriction and remodelling associated with PAH lead to overloading and hypertrophy of the right heart, and eventually to heart failure. While focusing on vasodilatation is an important part of effective management of PAH, it is increasingly apparent that the hypertrophic right heart is also a valid therapeutic target for intervention in the disease.
The PPARs (peroxisome proliferator activated receptors) have been shown in studies to be an attractive protective pathway in the overloaded heart. As well as protecting against ischemia reperfusion injury, in mice, PPAR has demonstrated effects on reducing left ventricular dilation, fibrosis and mitochondrial abnormalities. GW0742, a ligand which activates PPAR β selectively, has been shown in studies to reduce right heart hypertrophy without influencing pulmonary vascular remodelling. GW0742 is not currently used in the treatment of PAH. Nonetheless it is a feature of this invention that suitable formulations of GW0742 can be developed for loading into nano-particle delivery systems for lung, oral and intravascular administration.
Current treatments for PHA require that the therapy is administered by injection, or by inhalation. Inhalation would typically be preferred over injection, but current inhalable therapies require complex administration forms and schedules, and this has an effect on patient compliance or ease of delivery. Some therapeutics (for example, NO donors) require sustained release for effective administration.
The present invention proposes alternative formulations, which in some embodiments would be easier to administer.